Mefloquine selectively increases asynchronous acetylcholine release from motor nerve terminals
| Autor: | Kathleen M. Coakley, Joseph J. McArdle, Kormakur Hognason, Joseph G. Potian, Lawrence C. Sellin |
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| Rok vydání: | 2006 |
| Předmět: |
Thapsigargin
Oligomycin Neuromuscular Junction Presynaptic Terminals Action Potentials Motor nerve In Vitro Techniques Biology Pharmacology Antimalarials Mice Cellular and Molecular Neuroscience chemistry.chemical_compound Current clamp medicine Animals Drug Interactions Cholinergic synapse Enzyme Inhibitors Egtazic Acid Chelating Agents Mefloquine Acetylcholine chemistry Tacrine Calcium Oligomycins medicine.drug |
| Zdroj: | Neuropharmacology. 50:345-353 |
| ISSN: | 0028-3908 |
| DOI: | 10.1016/j.neuropharm.2005.09.011 |
| Popis: | Effectiveness against chloroquine-resistant Plasmodia makes mefloquine a widely used antimalarial drug. However, mefloquine's neurologic effects offset this therapeutic advantage. Cellular actions which might contribute to the neurologic effects of mefloquine are not understood. Structural similarity to tacrine suggested that mefloquine might alter cholinergic synaptic transmission. Therefore, we examined mefloquine's effects at a model cholinergic synapse. Triangularis sterni nerve-muscle preparations were isolated from adult mice and examined with sharp electrode current clamp technique. Within 30 min of exposure to 10 microM mefloquine, miniature endplate potentials (mepps) occurred in summating bursts and their mean frequency increased 10-fold. The threshold concentration for the increase of mean mepp frequency was 0.6 microM mefloquine. Mefloquine continued to increase mean mepp frequency for preparations bathed in extracellular solution lacking Ca2+. In contrast, mefloquine no longer increased mean mepp frequency for preparations pre-treated with the intracellular Ca2+ buffer BAPTA-AM. Although mefloquine disrupts a thapsigargin-sensitive neuronal Ca2+ store, pre-treatment with thapsigargin did not alter the mefloquine-induced alterations of mepps. Since mefloquine, like oligomycin, inhibits mitochondrial FOF1H+ ATP synthase we tested the interaction between these two chemicals. Like mefloquine, oligomycin induced bursts and increased mean frequency of mepps. Furthermore, pre-treatment with oligomycin precluded the mefloquine-induced alterations of asynchronous transmsitter release. These data suggest that mefloquine inhibits ATP production which increases the concentration of Ca2+ within the cytosol of nerve terminals. This elevation of Ca2+ concentration selectively increases asynchronous transmitter release since 10 microM mefloquine did not alter stimulus-evoked transmsitter release. |
| Databáze: | OpenAIRE |
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